Abstract A surprising, and lethal, observation is that addicts who are tolerant to high doses of opiates in an environment where they use these drugs habitually, can overdose when they take the drug in an unfamiliar environment. This phenomenon shows that a cognitive process, encoding environmental cues, can regulate the function of peripheral organs in a manner that could be the key to understanding a whole host of mind-body interactions that are important for survival. I propose that acetylcholine (ACh), acting through its receptors (nicotinic or nAChRs, and muscarinic or mAChRs) is uniquely placed to coordinate central cognitive processes, for example context-dependent learning, with autonomic and physiological processes we need for survival. More importantly, the big idea embedded in this proposal is that if ACh coordinates homeostatic responses between the brain and the periphery, not only does the brain control responses in the body, but changing the body can control cognition and behavior. If this is the case, it suggests that we can intervene in the periphery to induce opiate tolerance and prevent overdose, and maybe even treat opiate addiction. Using new molecular genetic tools, we will trace direct connections between precise cell types in the periphery and the brain, manipulate activity of peripheral and central neurons alone and in combination, regulate opioid receptor signaling in organs, peripheral neurons, central respiratory centers and brain areas involved in cognition, and determine the precise mechanisms for context-dependent opioid tolerance for the first time. We will go beyond the focus on specific neurons, one brain area, a single circuit or the brain in isolation, and begin to address the constant and complex interaction between the body and the brain that is essential for understanding how we are able to survive and adapt to a hostile environment. If this program is successful, I will move from being a molecular and behavioral neuroscientist to being an integrative physiologist, someone skilled in understanding the autonomic nervous system and a respiratory biologist, and my lab will be able to tackle mechanistic questions about brain-body interactions that were not approachable previously.